Cheng N, Maeda T, Kume T, Kaneko S, Kochiyama H, Akaike A, Goshima Y, Misu Y
Department of Pharmacology, Faculty of Phannaceutical Sciences, Kyoto University, Japan.
Brain Res. 1996 Dec 16;743(1-2):278-83. doi: 10.1016/s0006-8993(96)01056-6.
The neurotoxicity of L-DOPA and dopamine (DA) on striatal neurons was examined by using primary cultures of rat striatum. Exposure to L-DOPA and DA at concentrations of 30-300 microM induced dose-dependent cell death in both younger cultures (3 days in culture, 3 DIC) and elder cultures (10 days in culture, 10 DIC). The cytotoxicity of L-DOPA and DA was also dependent on the exposure time (6-24 h). Ascorbic acid (200 microM) inhibited both L-DOPA- and DA-induced cytotoxicity in 3 DIC cultures, whereas it provided significant protection against DA- but not L-DOPA-induced cytotoxicity in 10 DIC cultures. The L-DOPA cytotoxicity in 10 DIC cultures was prevented by a non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and by an NMDA receptor antagonist, MK-801. Neither antagonist prevented DA cytotoxicity. D-DOPA did not affect the viability of 10 DIC cultures, though it elicited marked toxicity in 3 DIC cultures. These results suggest that there are two components in the mechanisms that mediate the L-DOPA neurotoxicity on striatal neurons: one is autoxidation-relevant and the other is autoxidation-irrelevant. With respect to the latter, glutamate receptor stimulation may be involved. In contrast, autoxidation plays an important role in DA neurotoxicity.
利用大鼠纹状体原代培养物研究了左旋多巴（L-DOPA）和多巴胺（DA）对纹状体神经元的神经毒性。在年轻培养物（培养3天，3日龄）和年长培养物（培养10天，10日龄）中，暴露于浓度为30-300微摩尔的L-DOPA和DA均诱导了剂量依赖性细胞死亡。L-DOPA和DA的细胞毒性也取决于暴露时间（6-24小时）。抗坏血酸（200微摩尔）在3日龄培养物中抑制了L-DOPA和DA诱导的细胞毒性，而在10日龄培养物中它对DA诱导的细胞毒性提供了显著保护，但对L-DOPA诱导的细胞毒性没有作用。10日龄培养物中的L-DOPA细胞毒性可被非NMDA受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）和NMDA受体拮抗剂MK-801所阻止。两种拮抗剂均不能阻止DA的细胞毒性。D-DOPA对10日龄培养物的活力没有影响，尽管它在3日龄培养物中引发了明显的毒性。这些结果表明，介导L-DOPA对纹状体神经元神经毒性的机制中有两个成分：一个与自氧化相关，另一个与自氧化无关。就后者而言，可能涉及谷氨酸受体刺激。相比之下，自氧化在DA神经毒性中起重要作用。
